Behavioral studies of the aging rhesus monkey clearly demonstrate significant age-related functional changes that are likely to reflect cortical dysfunction. Yet observations from this program have demonstrated that there is no overt loss of neurons with age in either the cortex or the hippocampal formation nor is there a major loss of synapses. Thus it appears that neuron and synapse loss is not a major factor in age-related cortical dysfunction. In contrast, quantitative analysis of MRI images demonstrated a loss of subcortical white matter and EM studies by ourselves and colleagues have demonstrated an age- related increase in dystrophic myelin. This latter observation could reflect a primary damage to myelin or a response to changes in the neuron and its axon. Using PET imaging we have observed an age- related reduction in cortical blood flow and metabolism and subsequent analysis of brain tissue with markers for the oxidative enzyme cytochrome oxidase revealed an age-related reduction in these markers of neuronal metabolism. Based upon these findings, the overall objective of this project is to look at the cortical neuron to determine the type and extent of age-related changes that may underlie the age-related cognitive dysfunction that occurs in monkeys over 20 years of age. These studies will focus on the hippocampus/entorhinal cortex, area 17 of the visual system and area 46 of the prefrontal cortex. The specific experiments that will be conducted are: 1) To use histochemical and in situ hybridization methods to determine the extent of age-related changes in markers of oxidative metabolism. 2) To use on-the-slide receptor autoradiography to determine the extent and distribution of changes in selected neurotransmitter receptors. 3) To use the in vitro slice preparation for a neurophysiological investigation of synaptic responses, long term potentiation, membrane properties and neurotransmitter receptor responsivity to selected agonists and antagonists. In the course of these experiments neurons will be filled with biocytin and the extent of their dendritic tree analyzed morphologically. 4) To use electronmicroscopic methods to quantify the type and number of synapses in selected layers of areas 17, 46 and the entorhinal cortex. 5) To use electronmicroscopic methods to quantify the number of axons and their morphology in the fornix, anterior commissure and perforant path. 6) To use the optical disector and fractionator to estimate neuron number and determine if there is neuronal loss in selected areas. Together, these studies will establish the extent and generality of age-related changes in the function and connectivity of cortical neurons.